Roles of PABP1 in regulating mRNA-specific mRNA turnover
(A) Left: α-globin mRNA is protected from the action of ErEN and deadenylation (blunted arrows) by 3′-UTR CRE-associated αCP1–αCP2 complex which interacts with PABP1, promoting both CRE and poly(A) binding (double-headed arrow). Right: in the absence of the αCP1–αCP2 complex binding, ErEN can cleave within the CRE (zigzag arrow), PABP1 poly(A) binding will be reduced (broken arrow) and the cleaved mRNA fragments will be subject to decay. (B) Left: on non-translating c-fos mRNA, the mCRD is bound by UNR in complex with AUF1, PAIP1 and NSAP1. UNR (and possibly other complex components, depicted as broken arrows) interacts with PABP1 and inhibits c-fos mRNA deadenylation (blunted arrow) by an unknown mechanism. Right: upon translation of c-fos mRNA, the transiting ribosome displaces the UNR-containing complex from the mCRD, although it may remain associated with the poly(A) tail via PABP1 (broken arrow). UNR is then able to recruit CCR4–CAF1, and possibly also PAN2–PAN3 (not shown), to promote (+) deadenylation. (C) ARE-containing mRNAs are bound by one or more AUBPs. AUBPs can promote deadenylation directly through recruitment and stimulation of deadenylases and this can be antagonized by PABP1. AUBPs may also promote deadenylation indirectly by altering PABP1 poly(A) binding or modulating PABP1-mediated stimulation of deadenylases. Conversely, AUBPs may also inhibit deadenylation by enhancing PABP1 poly(A) binding and blocking its ability to stimulate deadenylase activity. Positive and inhibitory actions are depicted by + or − respectively. (D) PABP1 function is modulated during miRNA-mediated translational repression and deadenylation. RISC (only TNRC6 and Ago shown) is brought to the mRNA via miRNA complementarity. TNRC6 interacts with PABP1 directly (shown) and indirectly (not shown) and disrupts its interaction with eIF4G (broken arrow), an interaction which promotes the closed-loop conformation and may also enhance PABP1 poly(A) binding (not depicted). This results in repressed translation (blunted arrow), facilitating deadenylation. TNRC6 also directly recruits deadenylases and may bring them into close proximity to the poly(A) tail via its interaction with PABP1, to promote mRNA deadenylation (arrows). Deadenylase (A and C, see key) denotes events in which a specific deadenylase(s) has not been implicated.